This invention relates to ureidonitriles useful as antihypertensives.
Certain guanidine derivatives of tert-carbinamines possess antihypertensive (hypotensive) activity. Specific examples are tert-alkyl cyanoguanidines such as described by S. M. Gadekar, S. Nibi, and E. Cohen, J. Med. Chem., 11, 811 (1968); and various derivatives of tert-butyl guanidines as described by J. H. Short, C. W. Ours, W. J. Ranuse, Jr., J. Med. Chem., 11, 1129 (1968). Urea derivatives are not represented in general reviews of antihypertensive agents. These reviews include W. T. Comer and A. W. Gomoll, Medicinal Chemistry, Third Edition, A. Burger, Wiley Interscience, New York, 1970, pp. 1019-1064 and Medicinal Chemistry, Volume 7, "Antihypertensive Agents," E. Schlittler, Academic Press, New York, 1967.
Recently several patents claiming 1-tert-alkyl-3-(substituted cyclohexenyl)ureas (U.S. Pat. No. 4,002,767), 1-tert-alkyl-3-(substituted thienyl)ureas (U.S. Pat. No. 4,009,847), and 1-tert-alkyl-3-(substituted furyl)ureas (U.S. Pat. No. 3,969,370) as antihypertensive agents have appeared. The compounds of this invention differ structurally from these compounds since, e.g. (1) none of the above compounds contain a nitrile moiety, and (2) in all of the above cases the urea group is attached to an enolizable heterocyclic or carbocyclic ring system.
Many current antihypertensives produce unwanted side effects because of their undesirable mechanism of action. For example, guanethidine is an adrenergic neuron blocker, mecamylamine is a ganglion blocker, phenoxybenzamine is an .alpha.-adrenergic receptor blocker, and reserpine is a catecholamine depletor. Each of these mechanisms of action is undesirable because of the serious side effects produced.
The compounds of this invention appear to lower blood pressure by a desirable mechanism of action--direct peripheral vasodilation--and, therefore have a distinct advantage over the above undesirably-acting antihypertensives.
Furthermore, these compounds do not appear to produce central nervous system effects such as those seen with clonidine and .alpha.-methyldopa administration.